Autotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication

Autor: Michael J.O. Wakelam, Jane A. McKeating, Thomas F. Baumert, Simon A. Rudge, Maria Ciaccia, Laurent Mailly, Ke Hu, Margaret Ashcroft, Isla S. Humphreys, Stephanie Roessler, Bishnupriya Bhattacharya, Qifeng Zhang, Garrick K. Wilson, Michelle J. Farquhar, Gary M. Reynolds, Peter Balfe
Přispěvatelé: Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), NIHR Liver Biomedical Research Unit, University of Birmingham [Birmingham], Interaction virus-hôte et maladies du foie, Hepatitis C Research Group, Institute for Biomedical Research-University of Birmingham [Birmingham], Rudge, Simon Alan [0000-0003-2172-9709], Ashcroft, Margaret [0000-0002-0066-3707], Wakelam, Michael [0000-0003-4059-9276], Apollo - University of Cambridge Repository
Rok vydání: 2016
Předmět:
autotaxin
hepatitis C virus
0301 basic medicine
Hepatitis C virus
[SDV]Life Sciences [q-bio]
lipid signalling
Lysophosphatidic Acid Receptor
Hepacivirus
Biology
medicine.disease_cause
Virus Replication
Cell Line
03 medical and health sciences
chemistry.chemical_compound
Mice
Lysophosphatidic acid
medicine
Animals
Humans
RNA
Messenger
Receptors
Lysophosphatidic Acid
Promoter Regions
Genetic
ComputingMilieux_MISCELLANEOUS
Hepatology
hypoxia
Phosphoric Diester Hydrolases
Liver Neoplasms
[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
Hepatitis C
Chronic
Hypoxia-Inducible Factor 1
alpha Subunit
Virology
digestive system diseases
3. Good health
030104 developmental biology
chemistry
Autotaxin
lysophosphatidic acid
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Signal Transduction
Zdroj: Journal of Hepatology
Journal of Hepatology, Elsevier, 2017, 66 (5), pp.919-929. ⟨10.1016/j.jhep.2017.01.009⟩
ISSN: 1600-0641
0168-8278
DOI: 10.1016/j.jhep.2017.01.009⟩
Popis: BACKGROUND AND AIMS: Chronic hepatitis C is a global health problem with an estimated 170 million HCV infected individuals at risk of progressive liver disease and hepatocellular carcinoma (HCC). Autotaxin (ATX) is a phospholipase with diverse roles in physiological and pathological processes including inflammation and oncogenesis. Clinical studies have reported increased ATX expression in chronic hepatitis C, however, the pathways regulating ATX and its role in the viral life cycle are not well understood. METHODS: In vitro hepatocyte and ex vivo liver culture systems along with chimeric humanized liver mice and HCC tissue enabled us to assess the interplay between ATX and the HCV life cycle. RESULTS: HCV infection increased hepatocellular ATX RNA and protein expression. HCV infection stabilizes hypoxia inducible factors (HIFs) and we investigated a role for these transcription factors to regulate ATX. In vitro studies show that low oxygen increases hepatocellular ATX expression and transcriptome analysis showed a positive correlation between ATX mRNA levels and hypoxia gene score in HCC tumor tissue associated with HCV and other aetiologies. Importantly, inhibiting ATX-lysophosphatidic acid (LPA) signalling reduced HCV replication, demonstrating a positive role for this phospholipase in the viral life cycle. LPA activates phosphoinositide-3-kinase that stabilizes HIF-1α and inhibiting the HIF-signalling pathway abrogates the pro-viral activity of LPA. CONCLUSIONS: Our data support a model where HCV infection increases ATX expression that supports viral replication and HCC progression. LAY SUMMARY: Chronic hepatitis C is a global health problem with infected individuals at risk of developing liver disease that can progress to hepatocellular carcinoma. Autotaxin generates the biologically active lipid lysophosphatidic acid that has been reported to play a tumorigenic role in a wide number of cancers. In this study we show that Hepatitis C virus infection increases autotaxin expression via hypoxia inducible transcription factor and provides an environment in the liver that promotes fibrosis and liver injury. Importantly, we show a new role for lysophosphatidic acid in positively regulating hepatitis C virus replication.
Databáze: OpenAIRE
Externí odkaz: